New research published in the August issue of the Journal of Cell Biology explains for the first time why congenital heart defects so often occur with limb deformities.

In their research into the molecular mechanisms that control embryonic limb and heart development, Northwestern University researcher Hans-Georg Simon and his laboratory group recently identified a new protein, LMP4, which binds and regulates activity of the Tbx4 and Tbx5 transcription factors. Tbx5 and Tbx4 proteins play a key role in limb and heart formation in virtually all vertebrates, from fish to birds to mice to humans.

"Despite the importance in embryogenesis and disease, the mechanisms by which the transcription factors encoded by these genes exert their functions are not well understood," Simon said.

In studies using chicken and zebrafish model systems, Simon and his lab members are trying to gain a complete picture of how the Tbx and LMP4 proteins interact in order to control the growth and particular shaping of the limbs and heart.

LMP4 apparently regulates Tbx protein activity in the cell by keeping the Tbx transcription factors bound to the actin cytoskeleton or releasing them to the nucleus. Actin is a contractile protein of muscle and is a major component of the cytoskeleton  the "scaffolding" of the cell.

As the researchers wrote in their paper, this is the first demonstration of a Tbx transcription factor to be localized outside the cell nucleus by a specific protein. In addition, they demonstrate that removal of Tbx5 from the nucleus represses the transcription factor's ability to activate target genes in the limbs and heart.

"We are just beginning to understand the multitude of different cellular process that the Tbx proteins are involved in," concluded Simon. "The next step will be to identify the signals that regulate the dynamic interaction between LMP4 and Tbx5."